WO2016121954A1 - Nouveau sel de composé de pyrimidine condensé, et cristaux de celui-ci - Google Patents

Nouveau sel de composé de pyrimidine condensé, et cristaux de celui-ci Download PDF

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Publication number
WO2016121954A1
WO2016121954A1 PCT/JP2016/052733 JP2016052733W WO2016121954A1 WO 2016121954 A1 WO2016121954 A1 WO 2016121954A1 JP 2016052733 W JP2016052733 W JP 2016052733W WO 2016121954 A1 WO2016121954 A1 WO 2016121954A1
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compound
salt according
salt
crystal
powder
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PCT/JP2016/052733
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English (en)
Japanese (ja)
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宏美 鴛海
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大鵬薬品工業株式会社
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Priority to ES16743557.7T priority Critical patent/ES2667247T3/es
Priority to SG11201704431VA priority patent/SG11201704431VA/en
Application filed by 大鵬薬品工業株式会社 filed Critical 大鵬薬品工業株式会社
Priority to CA2974335A priority patent/CA2974335C/fr
Priority to DK16743557.7T priority patent/DK3115365T3/en
Priority to EP16743557.7A priority patent/EP3115365B1/fr
Priority to MX2017009864A priority patent/MX2017009864A/es
Priority to RU2017127128A priority patent/RU2702660C2/ru
Priority to KR1020177018432A priority patent/KR101852738B1/ko
Priority to JP2016533749A priority patent/JP6093486B2/ja
Priority to PL16743557T priority patent/PL3115365T3/pl
Priority to AU2016213031A priority patent/AU2016213031B2/en
Priority to BR112017016318-7A priority patent/BR112017016318B1/pt
Priority to MYPI2017701806A priority patent/MY196997A/en
Priority to CN201680007403.6A priority patent/CN107207517B/zh
Publication of WO2016121954A1 publication Critical patent/WO2016121954A1/fr
Priority to US15/297,180 priority patent/US9908889B2/en
Priority to PH12017501335A priority patent/PH12017501335A1/en
Priority to US15/861,947 priority patent/US10280174B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/15—Fumaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a novel salt of a compound having Bruton's tyrosine kinase (BTK) inhibitory activity and crystals thereof.
  • BTK Bruton's tyrosine kinase
  • Bruton's tyrosine kinase is a protein kinase belonging to Tec kinase family, and plays an important role in the control of proliferation, survival, differentiation and activation of B cells downstream of the B cell receptor (BCR) signal.
  • BCR B cell receptor
  • Non-receptor tyrosine kinase Non-patent Document 1. Inhibitors capable of controlling the activity of BTK are thought to be useful as therapeutic agents for diseases associated with abnormal enhancement of the BTK signal pathway (for example, cancer).
  • Non-patent Document 2 Non-patent Document 2
  • JAK3 Janus kinase 3
  • EGFR epidermal growth factor
  • apoptosis inhibition apoptosis inhibition
  • Non-Patent Document 4 PCI-45292 is known as a compound having BTK inhibitory activity and weak EGFR inhibitory activity (Non-patent Document 5).
  • An object of the present invention is to provide a highly selective BTK inhibitor having a high inhibitory activity against BTK, a low inhibitory activity against other kinases such as EGFR, and a salt useful as an active pharmaceutical ingredient. There is.
  • the applicant has studied the physicochemical properties of Compound A for the purpose of developing the formulation of Compound A.
  • Compound A When the free form of Compound A is exposed to high humidity, (2) Compound A is difficult to use as a drug substance because it absorbs the moisture in it and has the properties of a channel hydrate that releases moisture when exposed to low humidity.
  • Compound A More surprisingly, of these acid addition salts, only the fumarate salt of the channel hydrate is formed from only the tartaric acid, phosphoric acid and fumaric acid. It has been found that it has no properties, and the present invention has been completed.
  • the solid stability was poor, and the magnesium salt contained many related substances, so that the purity of the crystals was low.
  • Only the fumarate salt was found to be capable of avoiding the properties of channel hydrate, excellent in acquisition operability and reproducibility, stable and excellent in absorbability, and completed the present invention.
  • the present invention relates to the following 1) to 18).
  • Anti-tumor agent for blood tumor or fumarate of the above compound A for producing a prophylactic and / or therapeutic agent for allergic rhinitis, hay fever, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus Use of. 12) The fumarate salt of Compound A for use in BTK inhibition. 13) The fumarate salt of Compound A for use as a medicament. 14) The fumarate salt of Compound A for use in the prevention or treatment of tumors, allergic diseases, autoimmune diseases or inflammatory diseases.
  • the fumarate salt of Compound A for use in the prevention or treatment of blood tumors, allergic rhinitis, hay fever, atopic dermatitis, rheumatoid arthritis or systemic lupus erythematosus.
  • a method of inhibiting BTK comprising administering an effective amount of the fumarate salt of Compound A to a subject in need thereof.
  • a method for preventing and / or treating a tumor, allergic disease, autoimmune disease or inflammatory disease comprising administering an effective amount of the fumarate salt of Compound A to a subject in need thereof.
  • a method for treating blood tumors, allergic rhinitis, hay fever, atopic dermatitis, rheumatoid arthritis or systemic lupus erythematosus, wherein an effective amount of the fumarate salt of Compound A is administered to a subject in need thereof A method comprising:
  • the fumarate salt of compound A according to the present invention has excellent solid stability as an active pharmaceutical ingredient, and has the properties of channel hydrate compared to compound A or a salt other than fumarate salt of compound A. It can be avoided and has excellent operability and reproducibility. Furthermore, the fumarate salt of Compound A according to the present invention exhibits excellent oral absorbability and is extremely useful as a pharmaceutical product or drug substance.
  • 1 shows a powder X-ray diffraction spectrum of a monofumarate salt (amorphous) of Compound A synthesized in Example 1 (the vertical axis represents intensity (cps), and the horizontal axis represents the diffraction angle (2 ⁇ ⁇ 0.1 °).
  • 1 shows a powder X-ray diffraction spectrum of a 1 ⁇ 2 fumarate salt (crystal) of Compound A synthesized in Example 2 (the vertical axis indicates intensity (cps), and the horizontal axis indicates a diffraction angle (2 ⁇ ⁇ 0.1 °).
  • the differential scanning calorific value (DSC) curve of the 1/2 fumarate salt (crystal) of Compound A synthesized in Example 2 is shown.
  • the powder X-ray diffraction spectrum of the compound A monofumarate (crystal) synthesized in Example 3 shows the intensity (cps) and the horizontal axis shows the diffraction angle (2 ⁇ ⁇ 0.1 °).
  • the differential scanning calorific value (DSC) curve of the 1 fumarate salt (crystal) of Compound A synthesized in Example 3 is shown.
  • 2 shows a moisture absorption and desorption isotherm of Compound A.
  • 1 shows a moisture adsorption / desorption isotherm of a monofumarate salt (crystal) of Compound A.
  • the moisture adsorption-desorption isotherm curve of the 1/2 fumarate (crystal) of Compound A is shown.
  • the water adsorption-desorption isothermal curve of the 1/2 tartrate salt of Compound A is shown.
  • 2 shows a moisture adsorption / desorption isotherm curve of monophosphate of Compound A.
  • the effect of the mono-fumarate salt (crystal) of Compound A on a mouse collagen-induced arthritis model is shown.
  • a fumarate salt of compound A may be any salt form of compound A and fumaric acid, and includes 1 fumarate salt and 1/2 fumarate salt. . Furthermore, it is used in the meaning including both the crystal of the fumarate salt of Compound A and the amorphous form of the fumarate salt of Compound A.
  • the fumarate salt of Compound A preferably, the fumarate salt of Compound A (may be abbreviated as “Compound A • 1 Fumarate”) or the 1/2 fumarate salt of Compound A (“Compound A • 1 / Fumarate”) More preferably, it is abbreviated as “2 fumarate”, and more preferably, compound 1 monofumarate (crystal), compound A 1/2 fumarate (crystal), compound A 1 fumarate (non-fumarate) 1 fumarate salt (crystal) of Compound A and 1/2 fumarate salt (crystal) of Compound A are particularly preferred.
  • crystal and “amorphous” are used in the usual sense.
  • a plurality of crystals (crystal polymorphs) having different spatially ordered atomic arrangements and physicochemical properties may be formed, and the salt according to the present invention may be any of these crystal polymorphs, It may be a mixture of two or more crystal polymorphs, or a mixture of crystals and amorphous substances.
  • a label of the fumarate salt of Compound A that is, a compound in which one or more atoms of Compound A or fumaric acid are substituted with a radioactive isotope or a non-radioactive isotope is also encompassed in the present invention.
  • the diffraction angle and the overall pattern of the powder X-ray diffraction spectrum are important when the identity of the crystal is recognized due to the nature of the data. Since the relative intensity of the powder X-ray diffraction spectrum can vary somewhat depending on the direction of crystal growth, the size of the particles, and the measurement conditions, it should not be interpreted strictly. Numerical values obtained from various patterns may have some errors depending on the crystal growth direction, particle size, measurement conditions, and the like. Therefore, in this specification, the term “diffraction angle (2 ⁇ ⁇ 0.1 °)” in the powder X-ray diffraction spectrum means that the value may be within a range of ⁇ 0.1 ° of the value.
  • the word “near” used for the peak temperature of the endothermic peak in the differential scanning calorimetry (DSC) curve means that it is approximately the temperature value, and preferably within the range of ⁇ 5 ° C. of that value. That means it ’s good. More preferably, it means that it may be within a range of ⁇ 2 ° C. of the value.
  • the mono-fumarate salt (crystal) of Compound A preferably has a powder X-ray diffraction spectrum shown in FIG. 4 and / or a differential scanning calorimetry (DSC) curve shown in FIG.
  • the characteristic peaks in the powder X-ray diffraction spectrum of the monofumarate salt (crystal) of Compound A are 7.2 °, 12.4 °, and 15.6 as diffraction angles (2 ⁇ ⁇ 0.1 °). °, 25.9 ° and 27.6 °, more preferably 7.2 °, 12.4 °, 14.4 °, 15.0 °, 15.6 °, 19.0 °, Examples include 22.3 °, 22.6 °, 23.4 °, 25.5 °, 25.9 ° and 27.6 °.
  • the monofumarate (crystal) of Compound A according to the present invention is a crystal having at least two or more peaks selected from the above-mentioned more preferable peaks, and preferably at least three or more selected from the above-mentioned peaks
  • Particularly preferred are crystals having any of the above peaks.
  • the endothermic peak in the differential scanning calorimetry (DSC) curve of the mono-fumarate salt (crystal) of Compound A can be exemplified at around 219 ° C. to 224 ° C., preferably around 223 ° C.
  • the diffraction angle (2 ⁇ ⁇ 0.1 °) is 7.2 °, 12.4 °. , 15.6 °, 25.9 ° and 27.6 °, preferably at least 3 and more preferably 5 peaks in the differential scanning calorimetry (DSC) curve
  • the crystal has an endothermic peak with a peak temperature of about 219 to 224 ° C., preferably about 223 ° C.
  • the diffraction angle (2 ⁇ ⁇ 1 °) in the powder X-ray diffraction spectrum is 7.2 °, 12.4 °, 14.4 °, 15.0 °, 15.6 °. 19.0 °, 22.3 °, 22.6 °, 23.4 °, 25.5 °, 25.9 ° and 27.6 °, at least two, preferably at least three More preferably, at least 5 or more, more preferably at least 8 or more, more preferably any of the above peaks, and the peak temperature in the differential scanning calorimetry (DSC) curve is around 219 ° C. to 224 ° C., preferably Is a crystal having an endothermic peak around 223 ° C.
  • DSC differential scanning calorimetry
  • the 1/2 fumarate (crystal) of Compound A preferably has a powder X-ray diffraction spectrum shown in FIG. 2 and / or a differential scanning calorimetry (DSC) curve shown in FIG.
  • the characteristic peak in the powder X-ray diffraction spectrum of the 1/2 fumarate salt (crystal) of Compound A is 4.5 °, 5.8 °, 16 as the diffraction angle (2 ⁇ ⁇ 0.1 °). 6 °, 20.2 ° and 26.4 °, more preferably 4.5 °, 5.8 °, 11.2 °, 12.1 °, 12.4 °, 13.4. , 16.6 °, 17.3 °, 18.2 °, 20.2 °, 26.4 ° and 27.1 °.
  • the 1/2 fumarate salt (crystal) of Compound A according to the present invention is a crystal having at least two or more peaks selected from the more preferable peaks, and preferably at least three selected from the above peaks. A crystal having the above peaks, more preferably a crystal having at least 5 peaks selected from the above peaks, and more preferably a crystal having at least 8 peaks selected from the above peaks. Particularly preferred are crystals having any of the above peaks.
  • the endothermic peak in the differential scanning calorimetry (DSC) curve of the 1 ⁇ 2 fumarate salt (crystal) of Compound A is around 197 ° C to 199 ° C, preferably around 198 ° C.
  • the powder X-ray diffraction spectrum has a diffraction angle (2 ⁇ ⁇ 0.1 °) of 4.5 °, 5.
  • Differential scanning calorimetry (DSC) having at least 2 or more, preferably at least 3 or more, more preferably 5 peaks selected from 8 °, 16.6 °, 20.2 ° and 26.4 ° It is a crystal having an endothermic peak with a peak temperature in the curve of around 197 to 199 ° C., preferably around 198 ° C.
  • the diffraction angle (2 ⁇ ⁇ 1 °) in the powder X-ray diffraction spectrum is 4.5 °, 5.8 °, 11.2 °, 12.1 °, 12.4 °, 13. At least two selected from 4 °, 16.6 °, 17.3 °, 18.2 °, 20.2 °, 26.4 ° and 27.1 °, preferably at least three, more preferably Has at least 5 or more, more preferably at least 8 or more, more preferably any of the above peaks, and a peak temperature in a differential scanning calorimetry (DSC) curve is around 197 ° C. to 199 ° C., preferably 198 ° C. It is a crystal having an endothermic peak in the vicinity.
  • DSC differential scanning calorimetry
  • the fumarate salt of Compound A according to the present invention can also be obtained as an amorphous substance.
  • the amorphous form of the fumarate salt of Compound A according to the present invention specifically shows a halo pattern with a wide and unclear diffraction pattern in the powder X-ray diffraction spectrum, more preferably the powder X-ray diffraction shown in FIG. Has a spectrum.
  • Compound A can be synthesized, for example, according to Reference Examples 1 and 2 described later.
  • the synthesis method of Compound A is not limited to Reference Examples 1 and 2 described later. More specifically, (S) -tert-butyl 3- (methylsulfonyloxy) piperidine is obtained by reacting (S) -N-Boc-3-piperidinol with methanesulfonyl chloride in the presence of a tertiary amine such as triethylamine. -1-carboxylate is obtained.
  • the 1 fumarate salt (amorphous form) of Compound A according to the present invention can be produced, for example, by the following method. After adding 100 to 300 times, preferably 150 times the amount of tetrahydrofuran (THF) and 0.01 to 1 time, preferably 0.1 times the amount of water to Compound A, the same molar dose as Compound A is added. Add fumaric acid and dissolve. An amorphous form of the monofumarate salt of Compound A can be obtained as a white powder by distilling off the solvent while azeotroping with THF a plurality of times, preferably 2 to 5 times.
  • THF tetrahydrofuran
  • the compound A monofumarate (crystal) according to the present invention is, for example, a compound A monofumarate (amorphous) suspended in 5 to 50 times, preferably 20 times, acetonitrile. It can be obtained as a white powder by suspension heating for 12 to 72 hours, preferably 24 hours.
  • the 1 ⁇ 2 fumarate (crystal) of Compound A according to the present invention is, for example, a suspension of Compound A monofumarate (amorphous) in 10 to 100 times, preferably 60 times, methyl ethyl ketone. For 12 to 72 hours, preferably 24 hours, to obtain a white powder.
  • the channel hydrate property of Compound A can be avoided.
  • pharmaceuticals or active pharmaceutical ingredients that use compounds in which the properties of channel hydrate are avoided reduce storage and quality control problems in the storage conditions of humidity, and tablets, capsules, etc. It is known that when a solid preparation is produced, problems in the preparation based on the weight change of the active ingredient can be reduced. Therefore, the fumarate salt of Compound A according to the present invention can be expected to be stable storage and easy quality control, and can be said to be an excellent compound that is easy to handle in the preparation.
  • the fumarate salt of Compound A according to the present invention is excellent in acquisition operability and reproducibility as compared with other salts of Compound A. Specifically, for example, a salt of Compound A and hydrochloric acid, sulfuric acid, succinic acid, malic acid, citric acid, or acetic acid was not formed by the examination method described in this specification. In addition, for example, in the formation of the sodium salt of compound A, decomposition progressed remarkably, and when a 1 ⁇ 2 magnesium salt of compound A was synthesized, the number of related substances increased, and the operation for obtaining the salt was complicated. It was difficult to re-dissolve due to low solubility in water and organic solvents. The fumarate salt of Compound A according to the present invention is easy to handle as a drug substance and contributes to the industrial production of a stable quality drug.
  • the fumarate salt of Compound A according to the present invention is excellent in solid stability. It is important for drug development candidate compounds to have solid stability both in industrial operations and in maintaining quality. Therefore, the fumarate salt of Compound A according to the present invention has excellent properties required as a pharmaceutical or drug substance.
  • the fumarate salt of Compound A according to the present invention is excellent in oral absorbability and contributes to the provision of high quality and excellent pharmaceutical products.
  • the fumarate salt of Compound A according to the present invention has an excellent BTK inhibitory activity, for example, a preventive and / or therapeutic agent for cancer, tumor, various immune diseases (for example, allergic diseases, autoimmune diseases, inflammatory diseases). Useful as. In addition, it has excellent selectivity for BTK, and has the advantage that there are few side effects due to inhibition of other kinases (for example, EGFR).
  • BTK inhibitory activity for example, a preventive and / or therapeutic agent for cancer, tumor, various immune diseases (for example, allergic diseases, autoimmune diseases, inflammatory diseases).
  • BTK kinases
  • the fumarate salt of Compound A according to the present invention has excellent BTK inhibitory activity.
  • BTK includes human or non-human mammal BTK, preferably human BTK.
  • the term “BTK” includes isoforms.
  • the fumarate salt of Compound A according to the present invention is useful as a medicament for the prevention and treatment of diseases involving BTK due to its excellent BTK inhibitory activity.
  • Diseases involving BTK include diseases in which the rate of onset is reduced, symptoms are ameliorated, alleviated, and / or completely cured by deleting, suppressing and / or inhibiting BTK function. Examples of such diseases include, but are not limited to, cancer, tumor, allergic disease, autoimmune disease, inflammatory disease, graft-versus-host disease, and preferably cancer, tumor, allergic disease, It is an autoimmune disease.
  • the target cancer or tumor is not particularly limited.
  • epithelial cancer for example, respiratory cancer, digestive cancer, genital cancer, secretory cancer, etc.
  • sarcoma for example, hematopoietic cell line.
  • Tumors, central nervous system tumors, peripheral nerve tumors and the like, and hematopoietic cell tumors for example, leukemia, multiple myeloma, malignant lymphoma, etc. are preferable.
  • the type of tumor organ is not particularly limited, for example, head and neck cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, gallbladder / bile duct cancer, biliary tract cancer, pancreatic cancer, lung cancer, breast cancer,
  • Examples include ovarian cancer, cervical cancer, endometrial cancer, renal cancer, bladder cancer, prostate cancer, testicular tumor, bone / soft tissue sarcoma, blood tumor, multiple myeloma, skin cancer, brain tumor, mesothelioma and the like.
  • the hematopoietic cell line tumor is preferably acute leukemia, acute promyelocytic leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, lymphoblastic lymphoma, myeloproliferative tumor, chronic lymphocytic leukemia, small lymph Spherical lymphoma, myelodysplastic syndrome, follicular lymphoma, MALT lymphoma, marginal zone lymphoma, lymphoid plasma cell lymphoma, Waldenstrom macroglobulinemia, mantle cell lymphoma, diffuse large B-cell lymphoma, bar Kit lymphoma, extranodal NK / T cell lymphoma, Hodgkin lymphoma, multiple myeloma and the like.
  • B lymphoblastic leukemia / lymphoma follicular lymphoma, mantle cell lymphoma, nodal follicular marginal zone lymphoma, diffuse large B cell lymphoma, Burkitt lymphoma, chronic lymphocytic leukemia, small lymphocyte Blood tumors such as inflammatory lymphoma, Waldenstrom's macroglobulinemia, extranodal NK / T cell lymphoma, Hodgkin lymphoma, myelodysplastic syndrome, acute myeloid leukemia, acute lymphocytic leukemia.
  • the target allergic disease is not particularly limited, and examples thereof include bronchial asthma, allergic rhinitis, hay fever, atopic dermatitis, food allergy, anaphylaxis, drug allergy, urticaria and conjunctivitis.
  • bronchial asthma allergic rhinitis, hay fever and atopic dermatitis
  • particularly preferred are allergic rhinitis, hay fever and atopic dermatitis.
  • the target autoimmune disease is not particularly limited, and examples thereof include rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis, Sjogren's syndrome, and Behcet's disease.
  • Rheumatoid arthritis and systemic lupus erythematosus are preferable, and rheumatoid arthritis is particularly preferable.
  • the target inflammatory disease is not particularly limited.
  • a pharmaceutical carrier is blended as necessary, and various administration forms can be adopted depending on the purpose of prevention or treatment. May be any of oral preparations, injections, suppositories, ointments, patches, and the like. Each of these dosage forms can be produced by a conventional formulation method known to those skilled in the art. In particular, tablets for oral administration, coated tablets, pills, granules, powders, capsules, and stable solid preparations using crystals of the fumarate salt of Compound A as the active ingredient are advantageous.
  • the pharmaceutical carrier various organic or inorganic carrier substances commonly used as pharmaceutical materials are used. Excipients, binders, disintegrants, lubricants, coating agents, etc. in solid preparations, solvents in liquid preparations, dissolution aids , Suspending agents, isotonic agents, pH adjusting agents / buffering agents, soothing agents and the like. In addition, formulation additives such as preservatives, antioxidants, colorants, flavoring / flavoring agents, stabilizers and the like can be used as necessary. Examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, calcium silicate and the like.
  • binder examples include hydroxypropyl cellulose, methyl cellulose, polyvinyl pyrrolidone, candy powder, hypromellose and the like.
  • disintegrant examples include sodium starch glycolate, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, partially pregelatinized starch and the like.
  • lubricant examples include talc, magnesium stearate, sucrose fatty acid ester, stearic acid, sodium stearyl fumarate and the like.
  • coating agent examples include ethyl cellulose, aminoalkyl methacrylate copolymer RS, hypromellose, sucrose, and the like.
  • Examples of the solvent include water, propylene glycol, and physiological saline.
  • Examples of the solubilizer include polyethylene glycol, ethanol, ⁇ -cyclodextrin, macrogol 400, polysorbate 80 and the like.
  • Suspending agents include carrageenan, crystalline cellulose / carmellose sodium, and polyoxyethylene hydrogenated castor oil.
  • Examples of the isotonic agent include sodium chloride, glycerin, potassium chloride and the like.
  • Examples of the pH regulator / buffering agent include sodium citrate, hydrochloric acid, lactic acid, phosphoric acid, sodium dihydrogen phosphate and the like.
  • Examples of soothing agents include procaine hydrochloride and lidocaine.
  • preservatives include ethyl paraoxybenzoate, cresol, benzalkonium chloride, and the like.
  • antioxidant include sodium sulfite, ascorbic acid, natural vitamin E and the like.
  • colorant include titanium oxide, iron sesquioxide, edible blue No. 1, copper chlorophyll and the like.
  • flavoring and flavoring agents include aspartame, saccharin, sucralose, l-menthol, and mint flavor.
  • stabilizer include sodium pyrosulfite, sodium edetate, erythorbic acid, magnesium oxide, dibutylhydroxytoluene and the like.
  • an excipient When preparing an oral solid preparation, an excipient, if necessary, an excipient, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring / flavoring agent, etc. were added to the fumarate salt of Compound A Thereafter, tablets, coated tablets, granules, powders, capsules and the like can be produced by conventional methods.
  • tablets, coated tablets, granules, powders, capsules and the like can be produced by conventional methods.
  • When preparing injections add pH adjusters / buffers, stabilizers, tonicity agents, local anesthetics, etc. to the fumarate salt of Compound A, and use subcutaneous, intramuscular and intravenous methods by conventional methods. An injection can be produced.
  • the amount of the fumarate salt of Compound A to be incorporated in each dosage unit form is not constant depending on the symptoms of the patient to which the compound A is to be applied, or depending on the dosage form. It is desirable that the dosage is 0.05 to 1000 mg for an agent, 0.01 to 500 mg for an injection, and 1 to 1000 mg for a suppository.
  • the daily dose of the drug having the above dosage form varies depending on the patient's symptoms, body weight, age, sex, etc., and cannot be determined unconditionally, but is usually an adult (weight 50 kg) 1 as the fumarate salt of Compound A
  • the dose may be 0.05 to 5000 mg per day, preferably 0.1 to 1000 mg, and is preferably administered once a day or divided into 2 to 3 times a day.
  • the NMR spectrum was measured using an AL400 (400 MHz; JEOL), Mercury 400 (400 MHz; Agilent Technology) spectrometer, or an Inova 400 (400 MHz; Agilent Technology) spectrometer equipped with a 400M NMR probe (Protasis).
  • AL400 400 MHz; JEOL
  • Mercury 400 400 MHz; Agilent Technology
  • Inova 400 400 MHz; Agilent Technology
  • tetramethylsilane was used as an internal standard, and in other cases, measurement was performed using an NMR solvent as an internal standard, and all ⁇ values were shown in ppm.
  • Powder X-ray diffraction was measured according to the following test conditions after lightly grinding an appropriate amount of a test substance with an agate mortar as necessary.
  • DSC measurement Thermal analysis measurement (Differential scanning calorimetry (DSC measurement)) The DSC measurement was performed according to the following test conditions. Equipment: TA Instruments Q1000 Sample: Approximately 1 mg Sample container: made of aluminum Temperature rising rate: up to 250 ° C, 5 ° C / min. Atmospheric gas: Nitrogen Nitrogen gas flow: 50 mL / min. Handling of the device including data processing was in accordance with the method and procedure instructed by each device.
  • Step 1 Synthesis of (S) -tert-butyl 3- (methylsulfonyloxy) piperidine-1-carboxylate 20 g of (S) -N-Boc-3-piperidinol was dissolved in 100 mL of toluene and heated to 0 ° C. Then, 21 mL of triethylamine and 9.2 mL of methanesulfonyl chloride were added. After stirring for 1 hour under ice cooling, ethyl acetate and water were added, and the organic layer was separated.
  • the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, a saturated aqueous ammonium chloride solution and water, and then dried over anhydrous sodium sulfate.
  • the solvent was distilled off under reduced pressure to obtain 26.8 g of the title compound as a colorless solid.
  • Step 2 Synthesis of (R) -tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1-carboxylate
  • (S) -tert-butyl obtained in Step 1 A suspension of 150 mL of DMA containing 25 g of 3- (methylsulfonyloxy) piperidine-1-carboxylate and 69 g of potassium carbonate was heated to 100 ° C. and stirred for 10 hours. After cooling to room temperature, 300 mL of water was added and the resulting solid was collected by filtration, washed with water and dried to give 26.9 g of the title compound as a yellow solid.
  • Benz [d] oxazol-2-amine (118 mg), xanthophos (20 mg), and N-methylmorpholine (0.15 mL) were added for deaeration. Thereafter, 7.6 mg of palladium acetate was added, heated to 110 ° C. in a carbon monoxide atmosphere, and stirred for 2 hours. After cooling, methanol 4.5mL and 5N sodium hydroxide aqueous solution 0.45mL were added, and it stirred at room temperature for 30 minutes. Thereafter, the pH was adjusted to 5.3 with 2N HCl, and the resulting solid was collected by filtration. The crude product was purified by a silica gel column (chloroform-methanol) to obtain 257 mg of the title compound as a white solid.
  • Step 2 Synthesis of Compound A (R) -tert-butyl 3- (4-amino-3-((benzo [d] oxazol-2-yl) carbamoyl) -1H-pyrazolo [3,] obtained in Step 1 4-d] pyrimidin-1-yl) piperidine-1-carboxylate (5.0 g) was suspended in 50 mL of acetonitrile, and 7.85 g of sodium iodide was added. Under stirring at room temperature, 6.65 mL of trimethylsilyl chloride was added dropwise and stirred for 1 hour. After adding water 87.5mL and 5N sodium hydroxide aqueous solution 12.5mL, it ice-cooled.
  • Powder X-ray diffraction spectrum as shown in FIG.
  • Example 1 Monofumarate salt (amorphous form) (450 mg) of Compound A obtained in Example 1 was suspended in methyl ethyl ketone (27 mL), and suspended and heated at 80 ° C. for 24 hours. After filtration, the residue was dried under reduced pressure to obtain 1/2 fumarate (crystal) of Compound A as a white powder. Yield; 279 mg, yield; 62.0%
  • Powder X-ray diffraction spectrum shown in FIG. Characteristic diffraction angle (2 ⁇ ⁇ 0.1 °): 4.5 °, 5.8 °, 11.2 °, 12.1 °, 12.4 °, 13.4 °, 16.6 °, 17.3 °, 18.2 °, 20.2 °, 26.4 °, 27.1 °
  • DSC Differential scanning calorimetry
  • Example 1 Monofumarate salt (amorphous form) (500 mg) of Compound A obtained in Example 1 was suspended in acetonitrile (10 mL), and suspended and heated at 80 ° C. for 24 hours. Filtration and drying under reduced pressure gave Compound A monofumarate (crystal) white powder. Yield; 448 mg, yield; 89.6%
  • Powder X-ray diffraction spectrum shown in FIG. Characteristic diffraction angle (2 ⁇ ⁇ 0.1 °): 7.2 °, 12.4 °, 14.4 °, 15.0 °, 15.6 °, 19.0 °, 22.3 °, 22.6 °, 23.4 °, 25.5 °, 25.9 ° and 27.6 °
  • Differential scanning calorimetry (DSC) curves shown in FIG. Endothermic peak in differential scanning calorimetry (DSC) curve: around 219 ° C to 224 ° C
  • Test Example 1 Moisture Adsorption / Desorption Test Compound A obtained in Examples and Reference Examples, Compound A 1 fumarate, Compound A 1/2 fumarate, Compound A 1/2 tartrate, Compound A 1 The moisture absorption / desorption test of phosphate was conducted to examine the presence or absence of the properties of channel hydrate.
  • the moisture absorption / desorption test was measured according to the following conditions. Approximately 5 to 10 mg of the sample was filled in a dedicated quartz holder, and the weight of the sample at each humidity was continuously measured and recorded under the following conditions. In addition, the handling of the apparatus including data processing was in accordance with the method and procedure instructed by each apparatus.
  • VTI SA + manufactured by TA Instruments
  • Drying temperature 60 ° C
  • Temperature increase rate 1 ° C / min
  • Drying equilibrium Confirm that 0.01 wt% does not decrease in 5 minutes within a range not exceeding 300 minutes
  • Measurement temperature 25 ° C
  • Humidification equilibrium Confirm that 0.01 wt% does not increase in 5 minutes within a range not exceeding 120 minutes
  • Relative humidity program Increase by 5% RH from 5 to 95% RH, 5% from 95% RH to 5% RH Decrease by RH
  • the 1 fumarate salt of Compound A and the 1/2 fumarate salt of Compound A according to the present invention both increase in mass change of less than about 1% at 95% relative humidity, and lower the humidity. It turned out that it returned almost to the initial state. Therefore, it was confirmed that the fumarate salt of Compound A according to the present invention can avoid the properties of channel hydrate and has more excellent properties as a drug or drug substance.
  • Test Example 2 Solid stability test (acceleration test) Compound A monofumarate obtained in Examples and Reference Examples, Compound A 1/2 fumarate, Compound A 1/2 tartrate, Compound A monophosphate, 40 ° C./75% Solid stability when stored for 2 weeks or 4 weeks in RH (sealing condition and open condition) was measured under the following conditions.
  • Storage conditions 40 ° C./75% RH (sealed and opened) (open means that the glass bottle lid was removed and covered with Kimwipe) Measurement point: 2 weeks and 4 weeks Storage amount: about 30mg
  • Storage container Brown glass bottle
  • Sample solution preparation method The sample solution was dissolved in 50% acetonitrile so that the concentration of the sample was 0.4 mg / mL.
  • Table 4 shows the results of evaluating the total amount of related substances measured.
  • ⁇ indicates the ratio of the total amount of related substances of less than 0.1%, ⁇ indicates 0.1% or more and less than 0.5%, and ⁇ indicates 0.5% or more.
  • the * mark was measured in 2 weeks, and the others were measured in 4 weeks.
  • the mono-fumarate salt of Compound A and the 1 / 2-fumarate salt of Compound A produce less related substances, and are superior to the 1/2 tartrate salt of Compound A and the monophosphate salt of Compound A. It became clear that solid stability was exhibited. Therefore, it was confirmed that the fumarate salt of Compound A according to the present invention exhibits excellent solid stability.
  • Test Example 3 Solid stability test (severe test) Solid Stability when Compound A Monofumarate, Compound A 1/2 Tartrate, Compound A Monophosphate obtained in Examples and Reference Examples were stored at 60 ° C. for 2 weeks or 4 weeks Was measured under the following conditions. Storage conditions: 60 ° C (sealed) Measurement point: 2 weeks and 4 weeks Storage amount: about 30mg Storage container: Brown glass bottle Sample solution preparation method: The sample solution was dissolved in 50% acetonitrile so that the concentration of the sample was 0.4 mg / mL.
  • Table 5 shows the results of measuring and evaluating the amount of related substances in the sample solution by HPLC analysis in the same manner as in Test Example 2.
  • ⁇ indicates the ratio of the total amount of related substances of less than 0.1% and ⁇ indicates the ratio of 0.1% or more and less than 0.5%.
  • the * mark was measured in 2 weeks, and the others were measured in 4 weeks.
  • Test Example 4 Blood Concentration Measurement Test About Compound A, Compound A 1/2 fumarate, and Compound A monofumarate obtained in Examples, each of 0.5% HPMC was used. A suspension of 50 mg / 10 mL / kg in terms of molecular weight was prepared. These administration solutions were orally administered to mice (Balb / cA) kept under fed conditions at a dose of 10 mL per kg body weight using an oral administration sonde. After administration, the state was returned to the mouse cage and confirmed. In the cage, water supply and feeding were freely available.
  • mice were anesthetized with isoflurane, and blood was collected from a 60 ⁇ L orbital venous plexus using a capillary blood collection tube. The collected blood was ice-cooled and plasma was separated by centrifugation. After completion of blood collection, the mouse was returned to the animal breeding cage and the state after awakening of anesthesia was confirmed. After the final blood collection, the depth of isoflurane anesthesia was confirmed and then euthanized by cervical dislocation.
  • Test Example 5 Measurement of BTK Inhibitory Activity (In Vitro)
  • FL-Peptide 2 was added to PerkinElmer LabChip (registered trademark) series reagent consumables price list.
  • the purified recombinant human BTK protein used for the test was purchased from Carna Bioscience.
  • the monofumarate salt of Compound A was serially diluted with dimethyl sulfoxide (DMSO).
  • the substrate peptide (S) and the phosphorylated peptide (P) that were not phosphorylated with LabChip EZ Reader II (Perkin Elmer) were separated and detected by microchannel capillary electrophoresis.
  • the amount of phosphorylation reaction was determined from the peak heights of S and P, and the compound concentration capable of suppressing the phosphorylation reaction by 50% was defined as an IC50 value (nM) and is shown in Table 7 below.
  • Test Example 6 BTK inhibition selectivity compared with EGFR kinase inhibitory activity (in vitro) 1) Measurement of BTK inhibitory activity BTK inhibitory activity was measured in the same manner as in Test Example 5. 2) Measurement of EGFR inhibitory activity In the setting of the in vitro inhibitory activity measurement method for compounds against EGFR kinase activity, FL-Peptide 22 was measured in the lab kinase price list of Perchip Elmer LabChip (registered trademark) series. Since it was described that it corresponds as a substrate peptide, a biotinylated peptide (biotin-EEPLYWSFPAKKK) was prepared with reference to the amino acid sequence.
  • biotinylated peptide biotin-EEPLYWSFPAKKK
  • the purified recombinant human EGFR protein used for the test was purchased from Carna Bioscience.
  • the monofumarate salt of Compound A was serially diluted with dimethyl sulfoxide (DMSO).
  • DMSO dimethyl sulfoxide
  • the amount of fluorescence when irradiated with excitation light having a wavelength of 337 nm was measured at two wavelengths of 620 nm and 665 nm using PHERAstar FS (BMG LABTECH).
  • the amount of phosphorylation reaction was determined from the fluorescence amount ratio of two wavelengths, and the concentration of the compound capable of suppressing the phosphorylation reaction by 50% was defined as an IC50 value (nM).
  • IC50 value IC50 value
  • a test compound was calculated by calculating “EGFR inhibitory activity IC50 value (nM) / BTK inhibitory activity IC50 value (nM)”. The BTK inhibition selectivity was confirmed.
  • the BTK inhibition selectivity for EGFR kinase of the monofumarate salt of Compound A according to the present invention is about 13 times that of Comparative Compound 1 in vitro, and excellent BTK inhibition selectivity. It became clear to have. From these results, it was shown that the fumarate salt of Compound A according to the present invention can reduce side effects as compared with known BTK inhibitors.
  • Test Example 7 Growth Inhibitory Activity Measurement Test for BTK and EGFR-expressing Cell Lines (in Vitro) and Comparison of Selectivity TMD8 cells, which are a diffuse large B-cell lymphoma line expressing BTK, are 10% bovine. It was suspended in RPMI 1640 medium (Life Technologies) containing fetal serum. A431 cells, an EGFR overexpressing and highly activated human epidermoid carcinoma cell line, were suspended in DMEM and high glucose medium (Life Technologies) containing 10% fetal bovine serum. The cell suspension was seeded in each well of a 384 well flat bottom microplate and cultured at 37 ° C. for 1 day in an incubator containing 5% carbon dioxide gas.
  • the monofumarate salt of Compound A and Comparative Example Compound 1 were dissolved in DMSO, and the test compound was diluted with DMSO to a concentration 500 times the final concentration.
  • a DMSO solution of the test compound is diluted with the medium used for suspending each cell, and this is added to each well of the cell culture plate so that the final concentration of DMSO is 0.2%, and 5% carbon dioxide gas is contained.
  • Incubator was further cultured at 37 ° C. for 3 days. The cell count was measured before the addition of the compound and after the cultivation for 3 days in the presence of the compound using Celltiter Glo (manufactured by Promega) based on the protocol recommended by Promega.
  • the growth inhibition rate was calculated from the following formula, and the concentration of the test compound that inhibited 50% (GI50 (nM)) was determined.
  • A431 cell growth inhibition rate / TMD8 cell growth inhibition rate is calculated, and the larger the value, the higher the selectivity of BTK for EGFR in the cell.
  • Table 9 shows the value of “A431 cell growth inhibition rate / TMD8 cell growth inhibition rate”.
  • Test Example 8 Mouse collagen-induced arthritis model (therapeutic effect) This test was described in non-patent literature (Brand DD, et al., Nat Protoc. 2007; 2,1269-1275, Xu D. et al., JPET, 2012 Apr; 341 (1): 90-103). It carried out according to the method. 7-week-old male / DBA / 1 mice (Nippon Charles River) with 4 mg / mL bovine type 2 collagen solution (collagen technology workshop) and Freund's complete adjuvant (DIFCO) equal volume mixed solution (emulsion) 100 ⁇ L / body back skin Internal injection (primary immunization).
  • DIFCO Freund's complete adjuvant
  • day 0, day 3, day 7, day 10, day 14, day 17 were scored for signs of arthritis with the naked eye (0: no change, 1: swelling of one finger, 2: swelling of two or more fingers, 3: swelling of the upper, 4: swelling of all fingers and swelling of the wrists and ankles), and the total number of limbs was taken as the individual score (maximum 16 points).
  • the results are shown in FIG.
  • the prednisolone (3 mg / kg) administration group set as the positive target compound of the test system was able to maintain an elevated arthritis score, but the 1 fumarate salt of compound A according to the present invention (0.381 mg) / Kg) group effectively reduced the arthritis score. From this result, it was confirmed that the fumarate salt of Compound A according to the present invention has an excellent therapeutic effect on the already developed rheumatoid arthritis.

Abstract

Cette invention concerne un sel ayant une sélectivité élevée envers la BTK et qui est utile à titre de principe actif pharmaceutique. On a découvert qu'un fumarate de (R)-1-(1-acryloylpipéridin-3-yl)-4-amino-N-(benzo[d]oxazol-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide (composé A) représenté par la formule (1) n'a pas les qualités d'un canal hydrate, et est plus stable et mieux absorbé que le composé A et ses autres sels.
PCT/JP2016/052733 2015-01-30 2016-01-29 Nouveau sel de composé de pyrimidine condensé, et cristaux de celui-ci WO2016121954A1 (fr)

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MYPI2017701806A MY196997A (en) 2015-01-30 2016-01-29 Novel salt of fused pyrimidine compound and crystal thereof
KR1020177018432A KR101852738B1 (ko) 2015-01-30 2016-01-29 축합 피리미딘 화합물의 신규한 염 및 그 결정
CA2974335A CA2974335C (fr) 2015-01-30 2016-01-29 Nouveau sel de compose de pyrimidine condense, et cristaux de celui-ci
DK16743557.7T DK3115365T3 (en) 2015-01-30 2016-01-29 HIS UNKNOWN SALT OF CONDENSED PYRIMIDIDE COMPOUND AND CRYSTALS THEREOF
EP16743557.7A EP3115365B1 (fr) 2015-01-30 2016-01-29 Nouveau sel de composé de pyrimidine condensé, et cristaux de celui-ci
MX2017009864A MX2017009864A (es) 2015-01-30 2016-01-29 Sal novedosa de compuesto de pirimidina fusionado y cristal del mismo.
RU2017127128A RU2702660C2 (ru) 2015-01-30 2016-01-29 Новая соль конденсированного пиримидинового соединения и ее кристалл
ES16743557.7T ES2667247T3 (es) 2015-01-30 2016-01-29 Sal novedosa de compuesto de pirimidina condensado y cristal del mismo
JP2016533749A JP6093486B2 (ja) 2015-01-30 2016-01-29 縮合ピリミジン化合物の新規な塩及びその結晶
AU2016213031A AU2016213031B2 (en) 2015-01-30 2016-01-29 Novel salt of fused pyrimidine compound and crystal thereof
PL16743557T PL3115365T3 (pl) 2015-01-30 2016-01-29 Nowa sól skondensowanego związku pirymidynowego i jej kryształ
BR112017016318-7A BR112017016318B1 (pt) 2015-01-30 2016-01-29 Sal de ácido fumárico, inibidor de btk, composição farmacêutica e agente antitumoral compreendendo o dito sal e uso do dito sal
SG11201704431VA SG11201704431VA (en) 2015-01-30 2016-01-29 Novel salt of fused pyrimidine compound and crystal thereof
CN201680007403.6A CN107207517B (zh) 2015-01-30 2016-01-29 稠合嘧啶化合物的盐及其结晶
US15/297,180 US9908889B2 (en) 2015-01-30 2016-10-19 Salt of fused pyrimidine compound and crystal thereof
PH12017501335A PH12017501335A1 (en) 2015-01-30 2017-07-24 Novel salt of fused pyrimidine compound and crystal thereof
US15/861,947 US10280174B2 (en) 2015-01-30 2018-01-04 Salt of fused pyrimidine compound and crystal thereof

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WO2023232958A1 (fr) * 2022-06-01 2023-12-07 Alk-Abelló A/S Inhibiteurs de la kinase de bruton pour le traitement d'une réaction allergique soudaine

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US8673925B1 (en) * 2013-04-09 2014-03-18 Principia Biopharma Inc. Tyrosine kinase inhibitors
WO2015022926A1 (fr) * 2013-08-12 2015-02-19 大鵬薬品工業株式会社 Nouveau composé pyrimidine fusionnée ou son sel

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WO2021125313A1 (fr) 2019-12-19 2021-06-24 大鵬薬品工業株式会社 Agent thérapeutique contenant un composé de pyrimidine en tant que principe actif
JP7304968B2 (ja) 2019-12-19 2023-07-07 大鵬薬品工業株式会社 縮合ピリミジン化合物を有効成分とする治療剤

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